High Transfusion Burden Research Articles

Experience with luspatercept therapy in patients with transfusion-dependent low-risk myelodysplastic syndromes in real-world clinical practice: exploring the positive effect of combination with erythropoietin alfa.

Luspatercept, an inhibitor of the transforming growth factor beta (TGF-β) pathway, is a novel treatment for anemic patients with lower-risk myelodysplastic syndromes (MDS) with transfusion dependence (TD) who do not respond to erythropoiesis-stimulating agents (ESA) therapy or are not suitable candidates for this treatment. We present real-world experience with luspatercept therapy from two hematology centers in the Czech Republic. By January 2024, 54 MDS patients (33 men, 21 women) with a median age of 74 years (range, 55-95) were treated with luspatercept ± ESA at two Charles University hematology centers in Prague and Hradec Králové. According to the WHO 2016 classification, the cohort included 32 MDS-RS-MLD, seven MDS-MLD, two patients with 5q- + ring sideroblasts (RS), 12 RARS-T, and 1 patient with CMML-0 + RS. SF3B1 mutation data were available for 45 patients. All patients were in the IPSS-R and IPSS-M lower-risk groups (except four IPSS-M high). The median follow-up was 17 months (range, 1-54). All patients were transfusion-dependent. Thirty-five (64.8%) patients had a high transfusion burden (HTB) with ≥ 4 transfusion units (TU)/8 weeks, and 19 (35.2%) had a low transfusion burden (LTB) (< 4 TU/8 weeks). The median time between diagnosis and initiation of luspatercept was 27 months (range, 4-156). ESA were used prior to luspatercept in 45 patients, and luspatercept was used as first-line treatment in nine patients. Thirty-one (61%) patients were treated simultaneously with ESA. Only patients who received luspatercept for ≥ 8 weeks (51 patients) were assessed. We evaluated the achievement of transfusion independence (TI) lasting 8, 12, 16, and 24 weeks. Thirty-two (62.7%) patients achieved TI for ≥ 8 weeks, 31 (60.7%) for ≥ 12 weeks, 29 (56.8%) for ≥ 16 weeks, and 25 (49%) for ≥ 24 weeks. Hematologic improvement (HI) without TI was achieved in six patients (11.7%). Overall, HI + TI was achieved in 38 patients (74.5%). Epoetin alfa was used simultaneously in 31 patients (60.7%). In 21 (55.2%) of all responding patients, concomitant therapy with epoetin alfa led to an improved response, with 16 reaching TI. Thirteen (25.5%) patients were nonresponders. Eight (21%) patients experienced therapy failure and became transfusion-dependent again. Optimal response required a gradual increase in the luspatercept dose to 1.75 mg/kg in up to 35 patients, with 23 responders (TI + HI). Response rates varied by transfusion burden: 79% in LTB and 50% in HTB reached TI. Of RS+ patients, 70% reached TI, while only one out of five RS- patients achieved TI. Among 39 SF3B1-positive patients, 61.6% achieved TI. In the low and very low IPSS-M groups, 86% of patients responded (TI + HI), compared to 62% in the moderate-low group. Luspatercept was well-tolerated, with no adverse events higher than grade II toxicity. We have demonstrated in real-world clinical practice that luspatercept is a very effective agent, even in an unselected, pretreated, significantly TD MDS population. The effect was particularly high in the IPSS-M low and very low groups. We believe that the relatively high response rate in our patients was influenced by the frequent use of a higher dose (1.75 mg/kg) and especially by adding ESA to luspatercept in poorly responding patients.

Outpatient ATG-free hematopoietic transplantation for aplastic anemia in limited-resource environments offers excellent results: Data from a single LATAM center

ObjectiveTo document the results of outpatient hematopoietic stem cell transplantation (HSCT) from the peripheral blood (PB) of sibling donors without anti-thymocyte globulin (ATG) in the conditioning regimen. Material and methodsPatients from a low-income population with severe AA who received a PB, unmanipulated sibling HLA-identical HSCT between 2000 and 2020 at a single institution were studied. Survival was the primary outcome. ResultsForty-one transplants were performed. Time between diagnosis and transplant was five months (1–104). Median age was 37 (range, 4–61) years; 25 (61 %) recipients were males and 32 (78 %) had treatment failure, 9 (22 %) have not received treatment. ATG was administered in 5 (12.2 %) cases; the graft source was PB in 38 (92.7 %) transplants. Twenty-six (63.4 %) transplants were carried out in the outpatient setting. Infections developed in 14 (34.1 %) patients. Primary graft failure (GF) occurred in 3 (7.3 %) patients. The 15-year OS was 81 %, EFS was 77.4 %. Patients with high pre-HSCT transfusion burden had lower OS (p = 0.035) and EFS (p = 0.026). Previous treatment failure and age were not associated with lower OS (p = 0.115, p = 0.069) or EFS (p = 0.088, p = 0.5, respectively). ConclusionsHLA-identical T-cell replete outpatient HSCT from the PB of sibling donors for AA patients using ATG-free conditioning offers excellent long-term survival.

Care Patterns and Barriers to Outpatient Care for Adults With AML Following Intensive Chemotherapy at NCCN Member Institutions.

Prolonged hospitalization following intensive (re)induction chemotherapy for acute myeloid leukemia (AML), while standard, is costly and resource intense, limits inpatient bed capacity, and negatively impacts quality of life. Early hospital discharge (EHD) following completion of chemotherapy has proven safe as an alternative at select institutions, but is not widely implemented. From February 2023 through May 2023, the NCCN Best Practices Committee conducted a survey evaluating AML hospitalization patterns, care models, and barriers to EHD at its 33 member institutions. A total of 30 (91%) institutions completed the survey; two-thirds treat >100 patients with AML annually and 45% treat more than half of these with intensive chemotherapy. In the (re)induction setting, 80% of institutions keep patients hospitalized until blood count recovery, whereas 20% aim to discharge patients after completion of chemotherapy if medically stable and logistically feasible. The predominant reasons for the perceived need for ongoing hospitalization were high risk of infection, treatment toxicities, and lack of nearby/accessible housing. There was no significant association between ability to practice EHD and annual AML volume or treatment intensity patterns (P=.60 and P=.11, respectively). In contrast, in the postremission setting, 87% of centers support patients following chemotherapy in the outpatient setting unless toxicities arise requiring readmission. Survey responses showed that 80% of centers were interested in exploring EHD after (re)induction but noted significant barriers, including accessible housing (71%), transportation (50%), high toxicity/infection rate (50%), high transfusion burden (50%), and limited bed availability for rehospitalization (50%). Hospitalization and care patterns following intensive AML therapy vary widely across major US cancer institutions. Although only 20% of surveyed centers practice EHD following intensive (re)induction chemotherapy, 87% do so following postremission therapy. Given the interest in exploring the EHD approach given potential advantages of EHD for both patients and health care systems, strategies to address identified medical and logistical barriers should be explored.

Disease burden, management strategies, and unmet needs in α-thalassemia due to hemoglobin H disease.

Alpha-thalassemia is an inherited blood disorder caused by impaired α-globin chain production, leading to anemia and other complications. Hemoglobin H (HbH) disease is caused by a combination of mutations generally affecting the expression of three of four α-globin alleles; disease severity is highly heterogeneous, largely driven by genotype. Notably, non-deletional mutations cause a greater degree of ineffective erythropoiesis and hemolysis, higher transfusion burden, and increased complication risks versus deletional mutations. There are limited treatment options for HbH disease, and effective therapies are needed. This review discusses the pathophysiology of HbH disease, current management strategies, unmet needs, and emerging treatment options.

Improved Overall Survival Among Luspatercept Responders and Predictors of Response

Introduction Luspatercept (luspa) is a first-in-class erythroid-maturation agent approved for red blood cells transfusion dependent (RBC-TD) lower risk myelodysplastic syndrome (LR-MDS) with ring sideroblast (RS) based on MEDALIST clinical trial. We aimed to explore impact of luspa on overall survival (OS) and predictors of response in a large cohort of pts treated with luspa, collected from Moffitt Cancer Center (MCC) and from Fondazione Italiana Sindromi Mielodisplastiche (FISiM). Methods We evaluated all pts with LR-MDS-RS treated with luspa from MCC cohort since FDA approval, and from a multicenter observational trial of FISiM for pts treated on a compassionate use program . Baseline RBC transfusion burden (TB) was defined as: non-transfusion dependent (NTD) (0 units in 8 weeks prior luspa), low TB (LTB) (1-5 units/8 weeks ) and high TB (HTB) (≥ 6 units/8 weeks). A hematological response (HI) was defined as an (i) objective Hgb increase of &amp;gt; 1.5 g/dl in NTD, and (ii) RBC-TI with Hgb increase of 1.5 g/dl, or RBC-TI without Hgb 1.5 g/dl increase, or &amp;gt;50% reduction in RBC TB among RBC-TD. Somatic mutation (MT) data were available for 137 pts. Results Between January 2020 and March 2023, 331 pts were treated with Luspa (Table-1). The median age was 69 years; 308 pts (93%) had MDS-RS, 86,1% were intermediate, low or very low risk MDS by R-IPSS and 82% (105/128) were moderate low (ML), low (L) or very low (VL) by IPPS-M. SF3B1 MT was detected in 86.3% (120/139) with a median VAF of 37.7. The mean Hgb level was 7.97 g/dl and 93.7% were RBC-TD. Majority had prior erythroid stimulating agents (ESA) (93.6%). In the MCC cohort 42.9% (52/121) had prior hypomethylating agents (HMA) therapy, and 31.4% (38/121) had prior lenalidomide (len). With a median follow up of 14.6 mos from starting luspa treatment, the median OS was not reached (NR) among responders to luspa compared to 24.5 mos for non-responders (p &amp;lt;.001) (Figure-1). The median OS benefit was more pronounced among pts with RBC-TI and Hgb&amp;gt; 1.5 g/dl increase compared to other categories of response. In the NTD group at baseline, the median OS among luspa responders was NR compared to 22.7 mos among non-responders (P&amp;lt; .001). In the LTB group at baseline median OS was NR as well among luspa responders compared to 29.9 mos in non-responders (p=.002) and finally among HTB group at baseline, the median OS among luspa responders was 35.4 mos compared to 21.2 mos in non-responders (p=.007). In multivariable analysis adjusting for IPSS-M and baseline RBC-TD, response to luspa was independently associated with improved OS, HR .39 (95% CI .18-.83), p= .015 The overall HI rate to luspa was 40.6% (134/330) (Table-1), 85% of pts needed dose escalation, HI correlated with baseline RBC-TB where 80% (16/20) NTD, 60.2% (65/108) LTB and 41.8% HTB (77/184) achieved HI respectively, p&amp;lt; .001. By IPSS-M, there was a trend for lower HI with higher risk disease (100% in VL, 60.3% in L, 36.7% in ML, 56.3% in MH, 16.7% in H risk pts, p=.051). There was a mild trend for higher response among SF3B1 MT pts compared to wild type, 54% (64/119) versus 42% (8/19), p=.34.The segregation of SF3B1 MT cases into three independent groups based on IPSS-M, showed that HI rate was better in SF3B1 β ( SF3B1 and any gene from BCOR, BCORL1, NRAS, RUNX1, SRSF2 or STAG2) and SF3B1 α (as any other mutant) than SF3B1 5q(concomitantpresence with isolated del5q): 50% (7/14), 58.8% (57/97), and 0% (0/5) respectively, p=.03. Among SF3B1 5qpts, 4 had been treated with len before luspa and only 1 had achieved an HI with prior len. Among pts with SF3B1 MT, we observed a trend for higher response in pts with the hotspot K700E, 62.7% (37/59) vs 47.4% (27/57) in non-K700E, p=.097. In pts with SF3B1 MT, divided by median VAF, we observed a trend for better HI with VAF was &amp;gt;38, 63.5% (33/52) vs 45.3% (24/53), p=.062. Among responders, the median duration of response was 14.1 mos. As of last follow up, 85% pts (191/224) discontinued treatment. Reason of discontinuation was lack of response in 126 pts, loss of response in 26 patients and adverse events in 6 pts. The most common reported adverse events were fatigue (n=10), GI symptoms (n=4), shortness of breath and arthralgia (1 each). Conclusions Our RWD in the largest luspa treated cohort demonstrates OS benefit to luspa response. Low baseline RBC-TB dependency, lower risk IPSS-M, SF3B1 MT, SF3B1-K700E mutation and SF3B1 α co-mutations correlated with higher response rates. Our data emphasizes the impact of RBC-TI in LR-MDS.

Improvement of Patient-Reported Outcomes Among Heavily Pretreated Patients with Lower-Risk Myelodysplastic Syndromes and High Transfusion Burden Treated with Imetelstat on the IMerge Phase 3 Trial

CONCLUSIONS Transfusion-dependent anemia and related fatigue are commonly associated with lower-risk myelodysplastic syndromes (LR-MDS) and frequently not improved with therapy. Patients with symptoms associated with anemia have an impaired quality of life and inferior overall survival. In IMerge (NCT02598661), the phase 3, randomized, global trial of patients with LR-MDS and a red blood cell transfusion burden of ≥4 U, imetelstat-treated patients had a significantly higher transfusion independence rate than those treated with placebo and showed sustained improvement in patient-reported fatigue via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (Sekeres et al. EHA 2023. P732). Here, we assess the impact of imetelstat on several patient-reported outcomes (PROs) relevant to LR-MDS. Functional Assessment of Cancer Therapy-Anemia (FACT-An; 55 items) and Quality of Life in Myelodysplasia Scale (QUALMS; 38 items) were the main questionnaires used. Analyses included symptom-specific derived scores for the following parameters: dyspnea, measured by 1 FACT-An and 1 QUALMS item; physical function and systemic symptoms, by 3 FACT-An items each; pain, by 2 FACT-An items; and bleeding, by 1 QUALMS item. Higher scores indicated improvement. QUALMS total score and physical burden score were also analyzed. Psychometric analyses were conducted using blinded interim data to document the measurement properties of these item sets and define the scores that would be used to specify PRO end points in IMerge; all analyses were exploratory and were conducted in the intention-to-treat (ITT) population. The overall effect of imetelstat on each score was evaluated from the repeated measurement mixed model (RMMM) comparing the least-squares means (LSMs) of change in score estimated in the 2 treatment groups using all available data while on treatment up to cycle 30. A positive mean change in the dyspnea score was observed throughout the treatment, up to cycle 24, in the imetelstat group but not in the placebo group (Figure). The RMMM analysis showed an overall change in dyspnea score from baseline of 0.53 (by LSM with 95% CI, 0.241-0.825) with imetelstat versus −0.40 (by LSM with 95% CI, −0.794 to 0.003) with placebo, with a significant difference between the treatment groups (LSM difference, 0.93; 95% CI, 0.446-1.411; P &amp;lt; .001; Table). The model-based mean change estimates for each score showed that, despite having high transfusion burden at baseline, patients in the imetelstat group did not experience more deterioration in any of the other outcomes than those in the placebo group (Table). In addition, the QUALMS composite scores suggested significantly improved health outcomes with imetelstat versus placebo based on RMMM. LSM difference was 4.66 (95%CI, 0.862-8.461; P = .016) and 6.34 (95% CI, 1.771-10.913; P = .007) for QUALMS total and QUALMS physical burden, respectively (Table). Findings from multiple validated PRO questionnaires consistently show that patients with red blood cell transfusion-dependent LR-MDS enrolled into the IMerge randomized trial who were treated with imetelstat reported improved fatigue, dyspnea, and QUALMS composite scores (total and physical burden) compared with those in the placebo group. These data indicate that, in addition to improving transfusion burden in patients with LR-MDS, imetelstat targets multiple core symptoms of LR-MDS simultaneously, also improving PROs.

Care Patterns and Barriers to Outpatient Care for Adults with Acute Myeloid Leukemia (AML) Following Intensive Chemotherapy at National Comprehensive Cancer Network (NCCN) Institutions

Background: Prolonged hospitalization following intensive (re)induction chemotherapy until resolution of cytopenias is the current standard of care for adults with acute myeloid leukemia (AML), but this approach is costly, resource intense, contributory to hospital bed shortages, and negatively impacts patients' quality of life (QOL). Early hospital discharge (EHD) immediately following completion of chemotherapy has been proposed as an alternative and has proven safe at select institutions. Here, we conducted a National Comprehensive Cancer Center (NCCN) survey, through its Best Practices Committee (BPC), to examine discharge practices for adults with AML at other major cancer centers to better understand interest in, and barriers to, adopting an EHD approach more broadly. Methods: NCCN is a non-profit alliance of 33 cancer centers in the U.S. The survey was developed by 2 physicians at one center and piloted at 2 other centers. The NCCN BPC, which is composed of senior physician, nursing, and administrative leaders from NCCN Member Institutions, distributed the survey in early 2023 via a web-based survey tool (SurveyMonkey, San Mateo, CA) to a representative at each center, requesting completion by a content area expert. No incentives were offered for completion. Data were analyzed using descriptive statistics. Results: 30/33 (91%) centers completed the survey, 60% of which treat &amp;gt;100 AML patients annually and 45% treat over half of their patients with intensive chemotherapy (7+3 or regimens with a high-dose cytarabine backbone). All centers perform allogeneic hematopoietic cell transplantations (HCT). There was no difference in the proportion of intensively treated patients across centers by patient volume. Following (re)induction therapy, 80% of institutions keep patients hospitalized until blood count recovery, whereas 20% attempt to discharge patients early if medically stable and logistics permit. Concerns regarding patient safety, housing, and caregiver availability were the main reasons for keeping patients hospitalized ( Figure 1). In contrast, following post-remission (“consolidation”) therapy, 87% of centers discharge patients early. Concerns regarding increased care needs, worse functional status, and higher complications risks following induction relative to post-remission therapy accounted for the main reasons for this difference ( Figure 2). 80% of centers were interested in exploring EHD after (re)induction but noted barriers including affordable local housing (71%), transportation (50%), high toxicity/infection rate (50%), high transfusion burden (50%) and limited bed availability when re-hospitalization is necessary (50%). Among the 6 centers that practice EHD, all have infusion centers with full weekday hours, 5 have full weekend/holiday hours, 3 more have evening hours, and 1 has reduced holiday/weekend hours. All can provide blood product support within 4 hours from ordering and administer IV antimicrobials within 1 hour from ordering in outpatient clinic. In 4 centers, evaluation of a patient with presumed neutropenia contacting the clinic with fever during regular hours can occur in the outpatient clinic, with subsequent admission if necessary; at one center the patient would be referred to the ED and at one center the patient would be directly admitted to an inpatient ward. If a patient needs admission, a bed would be available for direct admission to the inpatient ward in 4/6 of the centers &amp;gt;75% of the time, at 1 center 26-50% of the time, and at 1 center &amp;lt;25% of the time. EHD was not practiced at any centers in cities with population of &amp;gt;1 million, citing local housing availability as a major EHD barrier. There was no correlation between the ability to practice EHD and annual AML patient volume, treatment intensity patterns, or hospitalization practices following HCT. Conclusions: Hospitalization and care patterns following AML therapy are highly variable across major U.S. cancer institutions. While only 20% of major cancer centers surveyed practice EHD following intensive (re)induction chemotherapy, 87% do so following post-remission therapy. There is interest in exploring this approach despite medical and logistical barriers. Given potential advantages of EHD for both patients and healthcare systems, strategies to address these barriers should be explored to reduce healthcare resource utilization and improve patients' QOL.

Durable Continuous Transfusion Independence (TI) with Imetelstat in IMerge Phase 3 for Patients with Heavily Transfused Non-Del(5q) Lower-Risk Myelodysplastic Syndromes (LR-MDS) Relapsed/Refractory (R/R) to or Ineligible for Erythropoiesis-Stimulating Agents (ESAs)

CONCLUSIONS MDS are serious life-threatening hematologic malignancies in which a heterogeneous group of clonal disorders results in ineffective hematopoiesis. An unmet need remains for new therapies for patients (pts) with LR-MDS who are red blood cell transfusion dependent (RBC-TD) and R/R to or ineligible for ESAs. Imetelstat, an oligonucleotide, is a first-in-class telomerase inhibitor that targets cells with high telomerase activity by direct binding to the RNA template of telomerase. In the IMerge phase 3 trial, imetelstat produced higher rates of TI for ≥8 weeks, ≥24 weeks, and ≥1 year (39.8%, 28.0%, and 17.8%) than placebo (15.0%, 3.3%, and 1.7%) in pts with non-del(5q) LR-MDS that was RBC-TD, R/R to/ineligible for ESAs, and naïve to lenalidomide or hypomethylating agents (HMAs; Platzbecker et al. EHA 2023. Abstr S165). We report characteristics and clinical benefit for pts with sustained TI for ≥1 year from this trial. IMerge (MDS3001, NCT02598661) is a global, double-blind, randomized, placebo-controlled, phase 3 trial of imetelstat in RBC-TD, ESA-R/R, non-del 5(q) lenalidomide/HMA-naïve LR-MDS. The primary end point was 8-week TI rate; secondary end points included safety, 24-week TI, duration of response, hematologic improvement, and MDS response. Exploratory end points included assessment of cytogenetic response and mutational status with clinical response. The proportion of pts with&amp;gt;1-year TI and other binary end points, were summarized with percentage and 95% 2-sided exact Clopper-Pearson CI. The Kaplan-Meier method was used to estimate the distribution of TI. Of 118 pts receiving imetelstat, 21 (17.8%; 95% CI, 11.4-25.9) achieved ≥1-year sustained TI, representing 45% of ≥8-week TI (21 of 47 pts) and 64% of ≥24-week TI (21 of 33 pts); of 60 pts receiving placebo plus supportive care, 1 (1.7%; 95% CI, 0-8.9) achieved ≥1-year TI. Of the ≥1-year TI imetelstat responders, 15/21 (71.4%) had ring sideroblasts, as did the 1 placebo pt. The median prior RBC transfusion burden was 6 U over 8 weeks (range, 4-9 U) for the imetelstat group and 5 U for the placebo pt. Additional baseline characteristics are in the table. Pts received imetelstat for a median of 101.1 weeks (range, 75.1-163.9 weeks) and a median of 24 cycles (range, 18-41 cycles). The median duration of TI for imetelstat ≥1-year TI responders was 123 weeks (95% CI, 80.4 to not evaluable); the median increase in hemoglobin during the longest TI interval was 5.18 g/dL (range, 2.67-13.76 g/dL) for the imetelstat group vs 1.67 g/dL for the placebo pt. After a median follow-up of 125 weeks, none of the patients with ≥1 year TI on either arm progressed to acute myeloid leukemia (AML). Of the pts receiving imetelstat, 7 had an abnormal karyotype at baseline, of which 6 had reduction in the cytogenetic abnormal clones (4 with cytogenetic complete response and 2 with cytogenetic partial response by independent review committee). Mutation data were available for 18 pts receiving imetelstat, all with SF3B1 mutations present at baseline, and multiple of these pts concurrently had TET2, DNMT3A, ASXL1, or JAK2 mutations. The maximal reduction ranged from −6% to −100% in SF3B1 variant allele frequency (VAF) in these pts, and 13 of 18 (72.2%) achieved ≥50% VAF reduction, including 7 with complete elimination of the VAF. Reduction in other concurrent mutations was also observed in these pts. Safety was consistent with that previously reported; most frequent adverse events were reversible grade 3 or 4 thrombocytopenia and neutropenia. At the time of data cutoff (May 10, 2023), 13 pts receiving imetelstat and the pt receiving placebo were ongoing (Figure); of the 8 who discontinued treatment, 7 had loss of response, and 1 was due to adverse event. Analyses for progression-free and overall survival were not evaluable as of this cutoff date (insufficient follow-up). Treatment with imetelstat resulted in ≥1-year sustained, continuous TI in 17.8% of pts in the IMerge phase 3 trial. In this ESA-R/R/ineligible population with a high prior transfusion burden, a reduction to 0 RBC transfusions for ≥1 year represents an opportunity to achieve relief from iron overload and other transfusion associated complications, and decreased demand on already limited blood product supply. Furthermore, durable TI and meaningful reductions in mutational burden suggest imetelstat may have disease-modifying activity.

Transfusions in autoimmune hemolytic anemias: Frequency and clinical significance of alloimmunization.

Autoimmune hemolytic anemia (AIHA) may be associated with transfusion reactions and risk of alloimmunization. To evaluate the transfusion policy and rate of alloimmunization and its clinical significance in AIHA. Data from 305 AIHA patients followed at a reference hematologic Center in Milan, Italy from 1997 to 2022 were retrospectively/prospectively collected (NCT05931718). Overall, 33% patients required transfusions with a response rate of 83% and eight transfusion reactions (7%), none hemolytic. Alloantibodies were detected in 19% of patients, being associated with higher transfusion burden (p=0.01), lower Hb increase post-transfusion (p=0.05), and transfusion reactions (p=0.04). Along decades, the rate of RBC transfusions decreased from 53% to 20% and that of alloimmunization dropped from 30% to 6% likely due to the adoption of prestorage leukoreduction, the use of more restrictive Hb thresholds, and the implementation of molecular typing. Severe symptomatic AIHA may be safely transfused provided appropriate matching of patients and donors.

Durable Clinical Benefit with Ker-050 Treatment: Findings from an Ongoing Phase 2 Study in Participants with Lower-Risk MDS

Background: In myelodysplastic syndromes (MDS), defects occur at multiple stages of hematopoiesis. Available Erythropoiesis Stimulating or Erythroid Maturation Agents (ES/EMAs) target early or late stages of erythropoiesis, respectively, and are only effective in subsets of patients. For patients with high transfusion burden (HTB) who have diminished erythropoietic capacity and a worse prognosis, ES/EMAs show limited efficacy and durability of response (DOR). KER-050 is an investigational, modified activin receptor type IIA ligand trap designed to inhibit select TGF-β superfamily ligands (activins A, B, GDFs 8, 11) that is being evaluated in diseases with ineffective hematopoiesis (IH), including MDS and myelofibrosis. Preclinical studies demonstrated that KER-050 increased erythropoiesis and thrombopoiesis and acted on early- and late-stage erythropoietic and megakaryocyte progenitors. By eliciting effects on hematopoiesis across multiple differentiation stages and cell lineages, KER-050 has the potential to address the complex nature of IH and to provide robust and sustained hematological improvement in patients with MDS who have limited treatment options, including those with HTB or non-ring sideroblast (RS) MDS. Methods: Analyses evaluating KER-050 at the recommended Part 2 dose (RP2D; 3.75 - 5 mg/kg q4wk) in participants with lower-risk (LR), RS+ or non-RS MDS from an ongoing Phase 2 study (NCT04419649) are presented as of a data cutoff date of April 3, 2023. The primary endpoint evaluates the safety and tolerability of KER-050. Secondary endpoints of modified IWG 2006 Hematological Improvement-Erythroid (HI-E) and transfusion independence (TI) ≥8 weeks are presented for participants who received ≥24 weeks of treatment or discontinued. DOR and changes in hematological parameters for participants with ongoing TI are presented for the first time. Results: At baseline, most participants receiving KER-050 at the RP2D (74.6%) required regular transfusions (≥2 RBC units/8 weeks); 52.5% of RP2D participants had HTB (≥4 RBC units/8 weeks) and 20.3% had ≥8 RBC units/8 weeks (Table 1). The median treatment duration was 166 days (range 6 to 649). Most participants (89.8%) had at least 1 treatment-emergent adverse event (TEAE), and 32.2% had TEAEs considered treatment-related (Table 1). The most frequently observed TEAEs in ≥15% of participants were fatigue (22.0%), nausea and diarrhea (18.6% each), epistaxis (16.9%), and COVID-19 and dyspnea (15.3% each). A minority of participants (10.2%) had TEAEs that led to treatment discontinuation. Consistent with prior data, rates of TI for ≥8 weeks were similar regardless of baseline transfusion burden or RS status (Table 1). Among TI responders, 72.7% maintained TI for ≥24 weeks (data not shown), and the median DOR was not yet evaluable as more than half (6/11) had ongoing TI as of the cutoff date (Figure 1). Five of the 6 (83.3%) participants with ongoing TI had HTB at baseline, including one participant with a baseline transfusion burden of 11 RBC units/8 weeks, and all 3 responders with ongoing TI for &amp;gt;60 weeks. One participant with HTB and non-RS MDS had ongoing TI for &amp;gt;72 weeks with a steady increase in hemoglobin from 8.4 to 11.8 g/dL. Erythroid responses were not at the expense of other cell lineages, as levels of platelets and neutrophils generally did not decrease (Figure 1). In fact, 44.1% of participants overall experienced a sustained (≥8 weeks) mean increase in platelet count of ≥30 x 10 9 within the first 24 weeks. Sustained decreases in ferritin were observed in parallel with increases in soluble transferrin receptor (Table 1), and for 3 participants, iron chelator therapy (ICT) was able to be discontinued. Investigation into changes in serum ferritin and ICT with KER-050 treatment will continue as cohorts of participants with MDS and iron overload are enrolled. Summary: Updated findings from this ongoing Phase 2 study in LR MDS continue to show that KER-050 is generally well-tolerated and has potential to elicit sustained hematological improvements in a broad population of participants with LR MDS, including those with HTB. New data reveal an encouraging DOR, with observed preservation or improvement of multilineage hematopoiesis and sustained decreases in ferritin manifesting clinically with discontinuation of ICT. The study is ongoing and an update with the latest data will be provided at the time of presentation.

Phase 1b/2 Study Evaluating the Safety and Efficacy of Canakinumab with Darbepoetin Alfa in Patients with Lower-Risk Myelodysplastic Syndromes (MDS) Who Have Failed Erythropoietin Stimulating Agents (ESA)

Introduction: Pyroptosis is a form of inflammatory, caspase-1 dependent lytic cell death mediated by inflammasome activation and ultimately leading to enumeration of pro-inflammatory cytokines, particularly interleukin 1β (IL-1β) and is a key driver of MDS pathogenesis (Basiorka A, Blood 2016). Release of IL-1β by pyroptotic cells leads to paracrine stimulation of neighboring hematopoietic and stromal cells resulting in amplification of this circuit, myeloid derived suppressor cell (MDSC) accumulation as well as direct suppression of erythropoiesis. Thus, we investigated the combination of the IL-1β neutralizing antibody canakinumab in combination with darbepoetin in patients with ESA refractory lower risk MDS and present the final dose phase 1b data. Methods: Patients ≥ 18 years old with IPSS-R very low to intermediate risk MDS who were ESA refractory and hypomethylating agent (HMA) naïve with adequate organ function were eligible. Patients must have been RBC transfusion dependent or hemoglobin &amp;lt; 9 gm/dl with symptoms. Treatment consisted of subcutaneous (SC) canakinumab on day 1 of a 28 cycle (150mg dose level 1, 300mg dose level 2) and darbepoetin SC 300µg days 1 and 15 of each cycle for a total of 6 cycles with continuation of therapy for responding patients. The phase 1b portion utilized a 3+3 dose escalation design with 6 patients treated at the maximum tolerated dose (MTD) to define the recommended phase 2 dose (RP2D). Bone marrow (BM) disease assessments occurred every 3 cycles with response defined by IWG 2018 criteria. Quality of life was assessed by QUALMS (Abel A, Haematologica, 2016). Peripheral blood mononuclear cells (PBMCs) were obtained at disease assessments and day 15 of C1 for evaluation of adapter protein apoptosis associated speck-like protein containing a CARD (ASC) specks as a biomarker of inflammasome formation with quantification as previously described (McLemore A, Pyroptosis: Methods and Protocols, 2023). Total IL-1β of BM plasma was assayed by ELISA. Results: Nine patients enrolled with a median age of 71 (range: 61-85 years), 67% female with baseline IPSS-R, IPSS-M and mutation data shown in Table. By IPSS-M, 3, 3, 1, 2 patients were low, moderately-low, moderately high, and high-risk categories. All IPSS-M lower risk mutant patients had splicing mutations. The median number of mutations was 2 (range 0-5). 100% of patients were ESA refractory. Additionally, 33% and 56% were refractory to lenalidomide and luspatercept therapy, respectively. Eight (89%) patients were PRBC dependent at baseline (56% [n=5] with high transfusion burden). The median follow-up duration was 6.1 months (range 3-17.8). The most common adverse events were neutropenia (n=7), followed by thrombocytopenia (n=4), and abnormal liver function tests (n=4). There were two grade 3 adverse events including thrombocytopenia and colitis, both unrelated to study treatment. There were no dose-limiting toxicities or serious adverse events in the phase 1 portion. All patients achieved the best response as stable disease, and no one had progression disease. No patients achieved objective response or significant reduction in transfusion burden. There was no statistical improvement in total QUALMS score from baseline to end of treatment (P=0.72) nor in the individual components (i.e. physical burden, benefit finding and emotional burden, P=0.69, P=0.91, P=0.630; respectively) although several patients had individual improvements. The percentage of PBMCs with ASC specks at baseline ranged from 0.3945-2.978% (median 1.93%). ASC specks decreased significantly after cycle 1 of therapy and were durably suppressed over the course of treatment in a majority of patients (Figure). Extracellular IL-1β in bone marrow plasma robustly increased with treatment and remained elevated (representing non-functional IL-1β [canakinumab bound IL-1β]; P=0.002 cycle 6 versus baseline), supporting pharmacodynamic effect with no differences observed between DL1 and DL2. Conclusions: The combination of canakinumab and darbepoetin was safe and well tolerated and 300mg of canakinumab is the RP2D. Canakinumab inhibited inflammasome activation as evidenced by a reduction of ASC specks although this did not translate to clinical responses. Phase 2 of the study will focus on patients with lower transfusion burden and molecular subsets with highest IL-1β expression (e.g. TET2/ DNMT3A mutant).

Overall Survival and Erythroid Response in Patients with Low-Risk Myelodysplastic Neoplasms after First-Line Treatment in a Low-Middle Income Country

Introduction Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and an increased risk of transformation to acute myeloid leukemia (AML). Current standard risk stratification model, the Revised International Prognostic Scoring System (IPSS-R), classifies patients into lower (≤3.5 points) or higher risk MDS. Lower-risk MDS (LR-MDS) treatment is based on the prevailing cytopenia and intends to improve symptomatic burden and minimize transfusion dependency. Anemia is present in 80-90% of patients with MDS. Throughout most of the course of the disease, patients with MDS have a hemoglobin &amp;lt; 10 g/dL, which leads to a decreased quality of life. Also, 50% of patients with MDS will eventually need red blood cell transfusions. Current options for the active treatment of anemia in LR-MDS are limited and vary among countries. Although erythropoiesis stimulating agents (ESAs) are considered standard of care in the absence of del5q, immunosuppressive therapy (IST) and androgens are still used in low income countries. The present study aims to evaluate whether erythroid responses and overall survival differ in patients with LR-MDS, based on their first-line treatment. Methods This is a retrospective study in patients with LR-MDS at Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, a tertiary care center in Mexico City. Eligible patients were diagnosed between January 2002 and December 2022 according to World Health Organization (WHO) 2016 criteria. Response was assessed according to International Working Group (IWG) 2018 criteria. We defined erythroid response (HI-E) as the sum of the responses achieved within different transfusion burden categories. First line therapy included ESAs, IST (cyclosporine ± eltrombopag), and androgens (mesterolone, danazol). These were compared through bivariate analysis, Kaplan-Meier curves and log-rank test. Results Until December 2022, 109 LR-MDS patients were considered for inclusion. Among them, 29 patients were lost to follow-up, and 25 patients were solely observed without any further therapy. Also, 7 patients who received other therapies were excluded. Ultimately, 48 patients were included in this analysis, 56.3% (n=27) were female, mean age was 62.8 (±15.9) years. Based on WHO 2016 classification, MDS with uni- and multilineage dysplasia was present in 58.3% (n=28) of the patients, while 29.2% (n=14) had hypoplastic MDS. Anemia was present in 89.6% (n=43) of the patients. When evaluating transfusion burden, 37.5% (n=18) of patients were non-transfusion dependent (NTD), 31.3% (n=15) low-transfusion burden (LTB), and another 31.3% (n=15) high-transfusion burden (HTB). ESAs and IST were the most frequently used frontline therapies, each accounting for 41.7% (n=20) of the patients; the remaining 16% (n= 8) received androgens. When comparing baseline characteristics between treatment arms, we found lower hemoglobin values and a greater proportion of severe anemia in ESA-treated patients (p= 0.039, p= 0.036), however, no differences in transfusion burden was observed (p= 0.212). Erythroid response rates were 25% (n=5), 20% (n=4) and 62.5% (n=5) among those treated with ESAs, IST and androgens, respectively (p= 0.071). When assessing HI-E by transfusion burden, no differences were observed between treatment arms except in HTB patients (p= 0.023). Neither time to response, nor duration of response were significantly different between treatment groups ( Table 1). Importantly, 3 of the 4 responders in the IST group received cyclosporine monotherapy, also 50% were hypoplastic MDS. After a median follow up of 47 months (IQR:22.5-85.5), the median overall survival(OS) for the entire cohort was not reached. The 3-year-OS rates for IST, ESA and androgens were 94%, 54% and 50%, respectively (p= 0.018) ( Figure 1). Conclusions In spite of the bias and limitations in the retrospective nature of this study, IST seems to be a valid option in frontline therapy for LR-MDS, since HI-E rates are similar to those observed with ESAs. Additionally, IST group showed a better OS. Results obtained with androgens merit further study and should be interpreted with caution because of the sample size.

Impact of preexisting autoimmune disease on myelodysplastic syndromes outcomes: a population analysis

AbstractPreexisting autoimmune disease affects between 10% and 30% of patients with myelodysplastic syndromes (MDS). Studies comparing outcomes in patients with MDS with and without autoimmune disease show discordant results. Using the Surveillance, Epidemiology, and End Results Medicare database, we conducted a population analysis to define the impact of autoimmunity on MDS outcomes. Cases were ascertained between 2007 and 2017 and claim algorithms used to identify autoimmune disease, demographic characteristics, comorbidity scores, MDS histology, transfusion burden, treatment with hypomethylating agents, and hematopoietic stem cell transplantation. Cox regression models estimated the impact on survival, and competing-risk regression models defined the effect on leukemic transformation. We analyzed 15 277 patients with MDS, including 2442 (16%) with preexisting autoimmune disease. The epidemiologic profile was distinctive in cases with preexisting autoimmunity, who were younger, were predominantly female, and had higher transfusion burden without difference in MDS histologic distribution. Autoimmune disease was associated with 11% decreased risk of death (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.85-0.94; P < .001). The effect on risk of leukemic transformation differed based on MDS histology. In low-risk MDS histologies, autoimmunity was associated with a 1.9-fold increased risk of leukemia (HR, 1.87; 95% CI, 1.17-2.99; P = .008), whereas no significant effect was seen in other groups. These results suggest that autoimmune disease affects survival in MDS and is associated with decreased mortality. The survival effect was evident in low-risk histologies despite higher risk of progression to leukemia. This could represent inflammation-driven hematopoiesis, simultaneously favoring less aggressive phenotypes and clonal expansion, which warrants further investigation.

Proinflammatory state promotes red blood cell alloimmunization in pediatric patients with sickle cell disease.

We examined risk factors for RBC alloimmunization in pediatric patients with sickle cell disease (SCD), focusing on recipients' inflammatory state at the time of transfusion and anti-inflammatory role of hydroxyurea (HU). Among 471 participants, 55 (11.70%) participants were alloimmunized and formed 59 alloantibodies and 17 autoantibodies with an alloimmunization rate of 0.36 alloantibodies per 100 units. Analysis of 27 participants who formed alloantibodies with specificities showed 23.8% (30/126) of units transfused during a proinflammatory event resulted in alloantibody formation compared to 2.8% (27/952) of units transfused at steady state. Therefore, transfusion during proinflammatory events increased the risk for alloimmunization (odds ratio [OR]: 4.22; 95% confidence interval [CI]: 1.64-10.85; p = 0.003). Further analysis of all the 471 participants showed alloimmunization of episodically transfused patients who received transfusion mostly during proinflammatory events was not reduced by HU therapy (OR: 6.52; 95% CI: 0.85-49.77; p = 0.071), HU therapy duration (OR: 1.13; 95% CI: 0.997-1.28; p = 0.056) or HU dose (OR: 1.06; 95% CI: 0.96-1.16; p = 0.242). The analysis also identified high transfusion burden (OR: 1.02; 95% CI: 1.003-1.04; p = 0.020) and HbSS and HbSβ0-thalassemia genotypes (OR: 11.22, 95% CI: 1.51-83.38, p = 0.018) as additional risk factors for alloimmunization. In conclusion, the inflammatory state of transfusion recipients affects the risk of RBC alloimmunization, which is not modified by HU therapy. Judicious use of transfusion during proinflammatory events is critical for preventing alloimmunization.

Efficacy and Safety of Luspatercept in Adult Patients with Transfusion-Dependent Anemia Due to Very Low, Low and Intermediate Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts, Who Had an Unsatisfactory Response to or Are Ineligible for Erythropoietin-Based Therapy: A Retrospective Multicenter Study By Fondazione Italiana Sindromi Mielodisplastiche (FiSiM ETS)

Background: Patients with lower-risk myelodysplastic syndromes (MDS) who develop red blood cells (RBC) transfusion-dependent anemia, experience worse quality of life and shorter survival. Therapeutic strategies after failure of erythropoiesis stimulating agents (ESAs) are limited. Regulatory approval of luspatercept in lower-risk MDS with ring sideroblasts (MDS-RS) offers a novel approach for the treatment of transfusion-dependent anemia in this subset of patients. However, data about luspatercept effectiveness in a real-world clinical setting are lacking. Here we report the results of a multicenter retrospective study including patients who were treated with luspatercept within the Italian compassionate use program. Methods: Eligible patients were ≥ 18 years old, had MDS-RS (2016 WHO classification), met criteria for very low, low, or intermediate IPSS-R risk; were receiving regular RBC transfusions (≥2 units/8 weeks in the 16 weeks before study entry); were refractory to or unlikely to respond to ESAs. Primary end point was transfusion independence (TI) for 8 weeks or longer during weeks 1 through 24; key secondary end point was TI for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. Other secondary end points included erythroid response (defined by the IWG 2006 criteria), progression to acute myeloid leukemia (AML) and safety analyses. Exploratory analyses were performed to identify predictive factors for treatment response. Results: 184 patients who were enrolled in the Italian luspatercept compassionate use program between December 2020 and December 2021 were analyzed in this study. Median age at enrollment was 74 years (range, 31-88), median time since diagnosis was 43 months, and median time since onset of transfusion-dependence was 23 months. Overall, 123 (66.8%) patients had at least one comorbidity requiring ongoing treatment, 39 (21.2%) had at least three. Baseline median transfusion burden was 6 RBC units every 8 weeks (range, 2-25). At the time of data analysis (June 30, 2022), 130 (73.4%) patients completed at least 24 weeks of treatment. Median time on treatment was 301.5 days, and median follow-up time was 376 days. During the first 24 weeks of the trial, 59 (32%) patients had TI for 8 weeks or longer. The percentage of patients achieving TI increased to 38.6% in the first 48 weeks of the trial. Median duration of TI was 27.9 weeks. Focusing on secondary endpoints, 36 patients (19.6%) had TI for 12 weeks or longer during the first 24 weeks, 52 (28.3%) had TI for 12 weeks or longer considering the first 48 weeks of the trial. A reduction ≥ 4 RBC units/8 weeks during weeks 1-24 was seen in 66 patients (40.2%). Four (2.2%) patients evolved to AML. Serious adverse events were recorded in 27 (15.2%) patients and led to study discontinuation in 5 (2.8%). Overall, treatment was discontinued in 72 (40.7%) patients, mainly for lack of benefit (table 1) The maximum approved dose (1.75 mg/kg) of luspatercept was administered at least once in 144 (81%) patients. Among patients who achieved TI for 8 weeks or longer in the first 48 weeks, luspatercept dose (mg/kg) at response was 1, 1.33 and 1.75 in 31 (46.3%), 18 (29.9%) and 18 (29.9%%) patients, respectively. Logistic regression analysis showed that higher baseline transfusion burden was significantly associated with a lower probability of achieving TI. We identified 3 group of patients stratified according to baseline transfusion burden (group 1, ≤4 units/8 weeks; group 2, 5 to 7 units/8 weeks, group 3, ≥8 units/8 weeks) with a significantly different probability to achieve both the primary endpoint (51.9%, 35.2% and 16.7%, respectively, P<0.01) and the key secondary endpoint (30.8%, 24.1% and 9%, respectively, P<0.01). Patients with higher transfusion burden had higher luspatercept doses at first response (table 2). In patients with low probability to achieve TI (group 2 and 3), a reduction in transfusions equal or greater than 4 units/8 weeks was achieved in 66 (46.2%). Conclusion: Luspatercept was effective for the treatment of transfusion-dependent anemia in MDS-RS in a real-life setting. The benefit extended beyond the achievement of TI and produced a significant reduction in the number of RBC transfusions. Higher baseline transfusion burden was associated with a reduced probability to achieve TI; in these patients, the reduction of transfused RBC units appears a more reliable treatment target. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Multiple Episodes of Transfusion Independence with Luspatercept Treatment and the Impact of Dose Escalation in Patients with Lower-Risk Myelodysplastic Syndromes from the MEDALIST Study

Introduction: In the phase 3 MEDALIST trial of luspatercept in lower-risk myelodysplastic syndromes (LR-MDS), 58 of 153 (37.9%) patients who received luspatercept achieved the primary endpoint of red blood cell (RBC) transfusion independence (RBC-TI) ≥ 8 weeks during weeks 1-24, versus 10 of 76 (13.2%) for placebo. Among the primary endpoint responders in the luspatercept arm, 17 (29.3%), 13 (22.4%), and 16 (27.6%) patients experienced 2, 3, or ≥ 4 separate RBC-TI ≥ 8 weeks response events during the entire treatment period, versus 3 (30%) and 1 (10%) patient in the placebo arm, who experienced 2 or 3 response events. (Platzbecker U, et al. Blood 2021;138:1524). The starting dose of luspatercept in the MEDALIST trial was 1.0 mg/kg with up-titration to 1.33 and 1.75 mg/kg allowed in the absence of RBC-TI after ≥ 2 doses at the same dose level, or after a loss of response following a dose reduction. Here, we report the effect of baseline transfusion burden (TB) and luspatercept dose level on response to treatment in patients with LR-MDS from the MEDALIST study. Methods: Eligible patients were ≥ 18 years of age, had LR-MDS requiring RBC transfusions, and were ineligible for, intolerant to, or refractory to erythropoiesis-simulating agents. Patients were stratified by mean baseline TB (mean RBC units/8 weeks assessed over the 16 weeks prior to initiation), as follows: low TB (LTB), > 0 to < 4 RBC units/8 weeks; intermediate TB (ITB), ≥ 4 to < 6 RBC units/8 weeks; and high TB (HTB), ≥ 6 RBC units/8 weeks. The number of individual periods of response (distinct episodes of RBC-TI ≥ 8 weeks) occurring during the entire treatment period was calculated. The treatment period lasted until the earliest of: the last dose date + 20 days; study discontinuation; data cutoff; or death. Time between RBC-TI responses was calculated as: start date of next response minus end date of current response plus 1. Results: As of November 26, 2020, RBC-TI ≥ 8 weeks was observed in 74/153 (48.4%) luspatercept patients and 12/76 (15.8%) placebo patients during the entire MEDALIST treatment period. Many patients experienced multiple distinct periods of RBC-TI ≥ 8 weeks; 52/74 (70.3%) luspatercept responders and 4/12 (33.3%) placebo responders experienced ≥ 2 episodes. The greatest number of response periods reported in a single patient was 10 with luspatercept and 3 with placebo. Overall, 30/39 (76.9%), 14/20 (70.0%), and 8/15 (53.3%) LTB, ITB, and HTB luspatercept responders, respectively, experienced ≥ 2 periods of response; 17/39 (43.6%), 10/20 (50.0%), and 5/15 (33.3%) LTB, ITB, and HTB luspatercept responders, respectively, experienced ≥ 3 periods of response; and 8/39 (20.5%), 3/20 (15.0%), and 0 LTB, ITB, and HTB, luspatercept responders, respectively, experienced ≥ 5 periods of response (Figure). The mean (SD) number of response periods with luspatercept was 3.0 (2.25) for LTB patients, 2.9 (2.0) for ITB patients, and 1.9 (1.03) for HTB patients. The greatest number of response periods reported with luspatercept in a single patient was 10 for LTB patients, 8 for ITB patients, and 4 for HTB patients. The mean (SD) time between RBC-TI response periods with luspatercept was 24.3 (63.16) days for LTB patients, 52.1 (55.91) days for ITB patients, and 32.1 (33.79) days for HTB patients. During the entire treatment period, rates of RBC-TI ≥ 8 weeks response at 1.0 mg/kg decreased with increasing baseline TB, with 94.9% of baseline LTB patients responding compared with 40.0% of baseline HTB patients. Patients who were ITB or HTB at baseline were more likely to respond when receiving 1.75 mg/kg luspatercept, with 50.0% and 46.7% responding, respectively, compared with 35.9% for LTB patients (Table). Conclusions: Patients who were LTB at baseline experienced more periods of RBC-TI response than ITB and HTB patients. LTB patients were more likely to respond to lower doses of luspatercept, whereas almost half of ITB and HTB patients required escalation to the maximum dose level to respond. ITB and HTB patients might be expected to wait longer for a second response to luspatercept than LTB patients. Importantly, many patients experienced multiple RBC-TI response periods with luspatercept, emphasizing the value of measuring cumulative response duration as well as the benefit of continuing luspatercept treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Luspatercept for Treatment of Lower Risk Myelodysplastic Syndromes: Real World Data Replicates Medalist Study Results and Confirms Activity Among Hypomethylating Agents and Lenalidomide Treated Patients

Introduction: Luspatercept, TGF-B fusion trap protein, is a first in class erythroid maturating agent approved by FDA for treatment of red blood cell transfusion dependent (RBC-TD) lower risk myelodysplastic syndromes (LR-MDS) with ring sideroblasts (RS) based on the MEDALIST clinical trial. Red blood cell transfusion independence (RBC-TI) was observed in 38% of 153 patients (pts) treated with luspatercept compared to 13% of 76 pts in the placebo group. We present to our knowledge first real-world data (RWD) in a large cohort of pts treated at our center with luspatercept for LR-MDS. More importantly, we address impact of prior therapies on response namely hypomethylating agents (HMA) as the original clinical trials excluded HMA treated pts. Methods We identified all pts treated at Moffitt Cancer Center with luspatercept since the FDA approval. Baseline RBC transfusion burden (TB) was defined as: non- transfusion dependent (NTD) (0 units in 8 weeks prior luspatercept), low TB (LTB) (1-5 units /8weeks) and high TB (HTB) (≥ 6 units /8 weeks). A hematological response (HI) was defined as an (i) objective Hgb increase of > 1.5 g/dl in NTD, and (ii) RBC-TI with Hgb increase of 1.5 g/dl, or RBC-TI without Hgb 1.5 g/dl increase, or >50% reduction in RBC transfusion burden among RBC-TD. Results Between February 2020 and December 2021, 114 pts were treated with luspatercept. Table-1 summarizes baseline characteristics in comparison to Medalist trial, the median age was 70 years. Seventy-three pts (67%) had MDS-RS subtype, 91% were intermediate or lower risk MDS by R-IPSS. SF3B1 mutation (MT) was detected in 71% (80/112). The mean Hgb level was 7.90 g/dl and 47% were RBC HTB transfusion dependent. The median serum erythropoietin (epo) level at time of referral was 122 U/L (19% > 500 U/L) (n=77). Majority had prior erythroid stimulating agents (ESA) (89%) with 29% hematological response to prior ESA, 59 pts (53%) had prior HMA therapy, and 42 patients (47%) had prior lenalidomide (len). The overall HI rate to luspatercept was 39.5% (45/114). Table-2 summarizes detailed responses. HI correlated with baseline RBC-TB where 69% (9/13) NTD, 47% (21/47) LTB and 25% HTB (13/53) achieved HI respectively, p=.004. Almost 55% of pts needed dose escalation, 62 pts received 1.33 mg/kg and 63 pts received 1.75 mg among whom 40% (25 pts) demonstrated response to higher doses. Based on RBC-TB, 75% (6/8) NTD patients achieved HI with highest dose escalation, 40% (10/25) LTB pts achieved HI with dose escalation and 30% (9/30) HTB pts achieved response with dose escalation. Among responders, the median duration of response was 15.6 months (2.6-27.3). As off last follow up, 56 pts (49%) discontinued treatment. Reason of discontinuation was lack of response in 47 pts, loss of response in 4 patients and adverse events in 5 pts (58 pts are still on therapy). The most common captured adverse events were fatigue (n=8), GI (n=4), shortness of breath and arthralgia (1 each). The response rates were higher among SF3B1 MT pts compared to wild type, 48% (34/80) compared to 16% (5/32), p=.002. The response rate among pts with RS subtypes versus non-RS were 49% versus 28% respectively, p=.05. Among 14 pts with MDS/MPN-RS-T the HI rate was 79%. HI for pts with serum epo < 500 U/L, was 48% (30/62) compared to 13% 2/15) for those with serum epo > 500, p=.01. Majority of pts with high serum epo level were RBC HTB at baseline 67% (10/15). The HI rate was 30% (18/60) after HMA failure compared to 50% (27/54) in HMA naïve pts, (p=.03). More pts post HMA failure were RBC-HTB 62% compared to 30% in HMA naïve. The luspatercept HI among RBC-LTB HMA failure pts was 39% compared to 54% in HMA naïve LTB, however, it was 24% among HTB HMA failure compared to 25% among HMA naïve HTB. The HI rate was 33% (15/46) for len failure pts compared to 43% (29/67) naïve patients, (p=.3). In multivariable analysis both SF3B1 mutation status and baseline RBC TB independently correlated with luspatercept response but not HMA failure. Conclusions Our RWD confirms luspatercept clinical benefit and safety profile observed in the MEDALIST trial. Responses are dose dependent with 1/3 of patients who were dose escalated responding. Low baseline RBC-TB dependency and SF3B1 MT correlated with higher response rates. Luspatercept retained activity after HMA or lenalidomide failure however a trend of lower responses observed correlated with RBC-HTB among those patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effects of Ker-050 on Iron Metabolism: Exploratory Analyses from an Ongoing Phase 2 Study in Patients with Myelodysplastic Syndromes

Background: Iron overload (IO) is an important clinical consequence of transfusion-dependent myelodysplastic syndromes (MDS). For patients with high transfusion burden (HTB), limited treatment options are available to effectively treat anemia and reduce transfusion dependence. Transfusion dependence is an independent predictor of poor prognosis in MDS. It is associated with IO and elevated ferritin, a marker of intracellular iron storage that also predicts poor prognosis in MDS. When adjusting for transfusion burden, each 500 µg/L increase in ferritin above 1000 µg/L is associated with a 30% greater risk of death (Malcovati et al. 2006). IO also disrupts osteoprogenitors and erythroid precursors within the osteohematopoietic niche, leading to abnormal bone turnover and ineffective erythropoiesis (Bulycheva 2015). While iron chelators have shown some efficacy in managing IO, they introduce toxicities and have little effect on transfusion burden. Unmet need remains for treatments that effectively address anemia, IO, and reduce transfusion dependence in patients with MDS, especially those with HTB. KER-050 is designed to alter signaling of TGF-β superfamily ligands, restoring balance to the osteohematopoietic niche, and promoting differentiation of erythroid and megakaryocytic precursors. It is a modified activin receptor type IIA ligand trap that inhibits TGF-β superfamily ligands, including activins A and B and growth and differentiation factors (GDFs) 8 and 11. To date, clinical data indicate that KER-050 induces sustained increases in reticulocytes and hemoglobin. Preliminary findings also show potential for KER-050 to induce erythroid response and reduce transfusion burden in patients with MDS, including those with HTB (Tan et al., 2022). KER-050 may also impact iron metabolism and this presentation explores the effects of KER-050 on indices of IO. Methods: This Phase 2 study is evaluating KER-050 in participants with very low- to intermediate-risk MDS. Data presented are from Part 1 Dose Escalation which included 16 weeks of KER-050 treatment across 5 cohorts (0.75 to 5 mg/kg). Iron chelator therapy was permitted at the discretion of the investigator provided patients had been on a stable dose for 8 weeks prior to C1D1. Markers of IO and hematopoiesis were assessed as exploratory endpoints over the 16-week treatment period. Analyses presented evaluate the effect of KER-050 on these markers. Baseline markers of bone turnover were also assessed. Results: A total of 31 patients were enrolled in Part 1 Dose Escalation; 26 were transfusion dependent, 18 with HTB (≥ 4 RBC units in 8 weeks prior to day 1). Seven HTB patients (38.9%) received iron chelator therapy. Baseline differences were noted in measures of iron status, erythropoiesis and bone turnover for non-transfused (NT), low transfusion burden (LTB), and HTB patients (Table 1). HTB patients had the highest baseline serum iron and ferritin levels. Preliminary findings indicate that KER-050 treatment was associated with decreases in serum ferritin for patients both with and without iron chelator therapy. Patients achieving transfusion independence (TI) experienced a 39.5% reduction (mean change: -619.4 ng/ml, range: -2118.4 to +243 ng/mL) in serum ferritin at Week 12 that was generally sustained at Week 16 and 20 (Figure 1). Similarly, over the same time period, serum iron and transferrin saturation (TSAT) decreased by 4.03 µmol/L (8.38%) and 5.3%, respectively, in patients achieving TI. Soluble transferrin receptor (sTfR) increased by 32.2% and remained elevated at subsequent visits. Summary: Preliminary data from the 16-week Dose Escalation in this ongoing phase 2 study reveal differences in baseline iron biomarkers indicative of increasing iron overload with increasing transfusion burden. While nearly half of HTB patients received iron chelator therapy, this group had markedly elevated ferritin compared to NT and LTB patients at baseline. KER-050 treatment was associated with reductions in serum ferritin, irrespective of the use of iron chelation. Patients achieving TI experienced decreases in ferritin, iron and TSAT concurrent with increases in sTfR that were generally maintained through follow-up. The data suggest that, in addition to improving hematopoiesis and transfusion burden in MDS patients, KER-050 may reduce iron overload, a serious clinical complication impacting the survival of these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Burden of β-Thalassemia: Findings from a Multinational Medical Record Abstraction Study

Introduction: β-thalassemias are rare genetic conditions characterized by mutations in the HBB gene, resulting in defective β-globin production and ineffective erythropoiesis. The severity of disease varies according to genotype. Periodic red blood cell transfusions (RBCTs) are the standard of care, but long-term dependence on RBCTs is associated with risk of iron overload and other clinical sequelae. As new treatment options are available, understanding the clinical burden of β-thalassemia and RBCTs is essential to optimal clinical care. Methods: This retrospective observational study analyzed anonymized medical records from adults (≥ 23 years of age) with transfusion dependent β-thalassemia (TDT) or non-transfusion dependent β-thalassemia (NTDT) who visited a participating physician on or after January 2016. Physicians in the UK, France, Germany, Spain, and Canada abstracted medical records for eligible patients with ≥ 5 years of medical history in their practice. Clinical characteristics, transfusion patterns, and RBCT utilization were analyzed descriptively. Results: A total of 214 patients were included: 118 (55%) with TDT and 96 (45%) with NTDT. Mean age was 36 years and body mass index was approximately 24 kg/m2 in both groups; 71% and 61% of patients with TDT and NTDT, respectively, were male. Mean (median) duration of patient medical history in the practice was 8.5 (7.5) and 8.6 (6.9) years for patients with TDT and NTDT, respectively. Among the TDT group, the mean (standard deviation [SD]) age at first diagnosis and first treatment of β-thalassemia was 11.1 (10.2) and 13.7 (11.2) years, respectively. The most common reasons for initiating RBCTs were: hemoglobin (Hb) levels < 8 g/dL (32%), < 7 g/dL (21%), < 6 g/dL (14%), and to maintain Hb > 10 g/dL (25%). The majority of patients (n = 87 [74%]) received β-thalassemia mutation testing; of these, 31 (36%) were β0/β0, 19 (22%) were β0/β+, and 23 (26%) were β+/β+. More than one-third (n = 41 [35%]) of patients with TDT had progressed from NTDT, at a mean (SD) age of 31.4 (11.7) years. The mean (SD) pre-transfusion Hb level in the TDT group was 6.9 g/dL (1.30) (n = 94). At the time of data abstraction, most patients with TDT (n = 90/118 [76%]) had an RBCT at least every 3 weeks (Figure 1), receiving a mean (SD) of 2.4 (0.64) RBC units (n = 101) per session. Approximately one-third (n = 43/118 [36%]) of patients with TDT received 3 RBC units per session, on average (Figure 2). Patients with TDT received their most recently reported RBCT regimen for a mean (SD) of 72.6 (72.43) months (n = 83). Adverse events (AEs) associated with the most recent transfusion regimen included allergic reactions (n = 3/118 [3%]), non-hemolytic febrile transfusion reactions (n = 2/118 [2%]), and transfusion-associated circulatory overload (n = 1/118 [1%]). Among the NTDT group, the mean (SD) age at first diagnosis and first treatment of β-thalassemia was 14.5 (11.8) and 18.8 (12.0) years, respectively. Approximately two-thirds (n = 63 [66%]) of patients with NTDT received β-thalassemia mutation testing; of these, 7 (11%) were β0/β0, 19 (30%) were β0/β+, and 20 (32%) were β+/β+. Among patients with NTDT, who had ≥ 1 RBCT (n = 81 [84%]), the mean (SD) number of RBCTs received was 15.9 (15.88) (in the physician's practice or as history noted in the medical record). The most common reasons for receiving RBCTs were: Hb levels < 8 g/dL (33%), < 7 g/dL (20%), and < 6 g/dL (14%), infection exacerbating anemia (16%), and to maintain Hb > 10 g/dL (15%). The mean (SD) pre-transfusion Hb level was 7.4 g/dL (1.18) (n = 67) and a mean (SD) of 2.2 (0.57) RBC units (n = 66) was transfused per session. AEs for patients with NTDT included allergic reactions (n = 4/96 [5%]), alloimmunization (n = 1/96 [1%]), autoimmune hemolytic anemia (n = 1/96 [1%]), and nonhemolytic febrile transfusion reaction (n = 1/96 [1%]). Conclusions: This study provides much needed insight into the real-world clinical needs of patients with β-thalassemia. About one-third of patients with TDT had progressed from NTDT. Patients with TDT had a high transfusion burden, requiring RBCTs every 2-4 weeks and 2-3 RBC units per session, on average. Additionally, patients with NTDT had low pre-transfusion Hb and required 2 RBC units per transfusion, on average. New therapeutic options are needed that can reduce RBCT dependency for patients with TDT, and improve pre-transfusion Hb levels and transfusion requirements for patients with NTDT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

First Single-Center Experience with Luspatercept Therapy in Low-Risk Myelodysplastic Syndrome (LR-MDS) Patients with Transfusion Dependence Refractory to Erythropoietin Therapy

Introduction: In the treatment of low-risk myelodysplastic syndromes (MDS) patients, anemia is the predominant problem. A recent breakthrough in the therapy of anemia in low-risk MDS patients are drugs involved in TGFβ pathway blockade. Luspatercept is a recombinant fusion protein derived from human activin receptor type IIB. It binds TGFβ superfamily ligands and inhibits the SMAD2/3 pathway leading to potentiation of red cell line differentiation and proliferation. Luspatercept was approved last year by the FDA and EMEA in the treatment of anemic low-risk MDS patients with ring sideroblasts (MDS-RS-MLD, MDS-RS-SLD) and/or SF3B1 mutated patients who are not eligible for erythropoiesis-stimulating agents (ESA) or for patients who failed on this therapy. Luspatercept showed high clinical activity for the treatment of anemia in the phase 2 trial (PACE-MDS) and subsequently in the phase 3 trial (MEDALIST). It has led to transfusion independence (TI) in about 40 % of patients. Methods: From January 2021 to July 2022, 27 patients were treated with luspatercept at the hematology department of Charles University Hospital in Prague, Czech Republic. The median age of the patients was 77 years (range 57-89) with a male to female ratio 17:10. WHO 2016 diagnosis were: MDS-RS-MLD (N = 23) and MDS/MPN-RS-T (N = 4). Median of IPSS-R was 2.5 (range 1-4). Median of IPSS-R cytogenetic score scaled from 0-2 with the median of 1. Median follow-up was 7.8 months (range 1-38). Luspatercept was administered in subcutaneous injections once every 3 weeks with an initial dose of 1 mg/kg. Dose escalation was done according to the level of response to 1.33 and 1.75 mg/kg. The median number of cycles administered was 7 (2-17). Transfusion dependency before luspatercept initiation ranged from 2 transfusion units (TU)/8 weeks to 12 TU/8 weeks, 11 patients had low transfusion burden (LTB), 16 high transfusion burden (HTB). Baseline erythropoietin (EPO) level was 374 IU/l in average (range 150-770) and ferritin level was 1307 μg/l in average (range 234-3832). 9 patients received chelation therapy. 22 patients were tested for SF3B1 mutation with 21 positive results (95.5 %) using Sanger sequencing (N = 3) or NGS approach (N = 18). Isolated mutation of SF3B1 was present in 8 patients (44 %). The most frequent mutations besides SF3B1 were TET2 (N = 8; 44 %), ASXL1 (N = 3; 17 %), DNMT3A and RUNX1 (N = 2; 11 %). Average mutations count per one patient was 1.7 (range 0-5). We did not observe any TP53 mutation. Results: There were 24 evaluable patients in terms of response. Thus far 11 (45 %) patients have responded by achieving TI, 5 (20 %) patients have had a reduction in transfusion dependence (HI, according to IWG criteria 2006), 8 (33 %) patients have not responded. One patient progressed to the higher risk MDS, and one transformed to acute myeloid leukemia. Median duration of response was 7.4 months (range: 0.7-31.8). Median number of cycles to achieve response was 4. Eleven patients responded to the basic dose 1 mg/kg, 2 additional patients on the dose 1.33 mg/kg and 2 more on the dose 1.75 mg/kg. There were differences in response according to transfusion burden, in LTB group achieved TI 8 patients and HI 1 patient, in HTB group we observed TI in 3 patients and HI in 4 patients. In 9 patients, we added ESA to luspatercept therapy, as they act both at different levels of erythropoiesis, which led to the improvement of response in 5 cases. In general, patients with lower initial baseline EPO level were better responders. We did not observe decrease in ferritin level during therapy. There was no significant effect of mutation burden on patient's OS, although patients with single mutated SF3B1 achieved better ORR (75 %), than patients bearing mutations in multiple genes (ORR = 40 %). There were no adverse effects of Grade II or more. Conclusion: In conclusion, luspatercept is certainly the next major step in the treatment of anemia in MDS patients. The advantage of the drug is very good tolerance and easy administration. We observed better responses in patients bearing single mutation in SF3B1, patients with LTB and lower initial baseline EPO levels. The higher response rate in our follow-up may be influenced by the combination with ESA and rapid dose escalation. This work was supported by the following grants: grant AZV 2021-2024 NU21-08-00312, Grant AZV 2019-2023 NV19-08-00144, UNCE/MED/016